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https://www.readbyqxmd.com/read/28197367/targeting-ewing-sarcoma-with-activated-and-gd2-specific-chimeric-antigen-receptor-engineered-human-nk-cells-induces-upregulation-of-immune-inhibitory-hla-g
#1
Sareetha Kailayangiri, Bianca Altvater, Christian Spurny, Silke Jamitzky, Sonja Schelhaas, Andreas H Jacobs, Constanze Wiek, Katharina Roellecke, Helmut Hanenberg, Wolfgang Hartmann, Heinz Wiendl, Susann Pankratz, Jutta Meltzer, Nicole Farwick, Lea Greune, Maike Fluegge, Claudia Rossig
Activated and in vitro expanded natural killer (NK) cells have substantial cytotoxicity against many tumor cells, but their in vivo efficacy to eliminate solid cancers is limited. Here, we used chimeric antigen receptors (CARs) to enhance the activity of NK cells against Ewing sarcomas (EwS) in a tumor antigen-specific manner. Expression of CARs directed against the ganglioside antigen GD2 in activated NK cells increased their responses to GD2+ allogeneic EwS cells in vitro and overcame resistance of individual cell lines to NK cell lysis...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28175613/369%C3%A2-chimeric-antigen-receptors-deficient-in-lck-signaling-require-4-1bb-costimulation-to-expand-in-vivo-resist-regulatory-t-cell-suppression-and-treat-solid-tumors-in-immune-intact-hosts
#2
Carter M Suryadevara, Rupen Desai, Samuel Harrison Farber, Patrick C Gedeon, Adam Swartz, David Snyder, James Herndon, Patrick Healy, Bryan D Choi, Peter Edward Fecci, Luis Sanchez-Perez, John H Sampson
No abstract text is available yet for this article.
August 1, 2016: Neurosurgery
https://www.readbyqxmd.com/read/28129128/aptamer-targeted-attenuation-of-il-2-signaling-in-cd8-t-cells-enhances-antitumor-immunity
#3
Anugraha Rajagopalan, Alexey Berezhnoy, Brett Schrand, Yvonne Puplampu-Dove, Eli Gilboa
Immune responses elicited against cancer using existing therapies such as vaccines or immune stimulatory antibodies are often not curative. One way to potentiate antitumor immunity is to enhance the long-term persistence of anti-tumor CD8(+) T cells. Studies have shown that the persistence of activated CD8(+) T cells is negatively impacted by the strength of interleukin 2 (IL-2) signaling. Here, we used small interfering RNAs (siRNAs) against CD25 (IL-2Rα) to attenuate IL-2 signaling in CD8(+) T cells. The siRNAs were targeted to 4-1BB-expressing CD8(+) T cells by conjugation to a 4-1BB-binding oligonucleotide aptamer...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28115575/the-egr2-targets-lag-3-and-4-1bb-describe-and-regulate-dysfunctional-antigen-specific-cd8-t-cells-in-the-tumor-microenvironment
#4
Jason B Williams, Brendan L Horton, Yan Zheng, Yukan Duan, Jonathan D Powell, Thomas F Gajewski
Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous antitumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms, but also a T cell-intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining tumor-specific dysfunctional TILs, and PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro...
February 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28115358/therapeutic-efficacy-of-4-1bb-costimulation-is-abrogated-by-pd-1-blockade-in-a-model-of-spontaneous-b-cell-lymphoma
#5
Sara McKee, Brianna L Doff, Megan Sf Soon, Stephen R Mattarollo
Combinations of monoclonal antibodies (mAb) that target various components of T-cell activation/inhibition may work synergistically to improve antitumor immunity against cancer. In this study we investigated the therapeutic potential of combining an anticancer vaccination strategy with antibodies targeting an immune stimulatory (4-1BB) and immune inhibitory (PD-1) receptor, in a preclinical model of spontaneously arising c-Myc-driven B-cell lymphoma. In Eμ-myc transgenic mice we reveal that 4-1BB agonistic mAb treatment alone was sufficient to drive antitumor immunity and prevent disease progression in 70% of mice...
January 23, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28074529/epigenetic-mediated-immune-suppression-of-positive-co-stimulatory-molecules-in-chemoresistant-ovarian-cancer-cells
#6
Ercan Cacan
The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity...
January 11, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28067900/donor-cd19-car-t-cells-exert-potent-graft-versus-lymphoma-activity-with-diminished-graft-versus-host-activity
#7
Arnab Ghosh, Melody Smith, Scott E James, Marco L Davila, Enrico Velardi, Kimon V Argyropoulos, Gertrude Gunset, Fabiana Perna, Fabiana M Kreines, Emily R Levy, Sophie Lieberman, Hillary V Jay, Andrea Z Tuckett, Johannes L Zakrzewski, Lisa Tan, Lauren F Young, Kate Takvorian, Jarrod A Dudakov, Robert R Jenq, Alan M Hanash, Ana Carolina F Motta, George F Murphy, Chen Liu, Andrea Schietinger, Michel Sadelain, Marcel R M van den Brink
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies...
February 2017: Nature Medicine
https://www.readbyqxmd.com/read/28051085/intrinsic-4-1bb-signals-are-indispensable-for-the-establishment-of-an-influenza-specific-tissue-resident-memory-cd8-t-cell-population-in-the-lung
#8
A C Zhou, L E Wagar, M E Wortzman, T H Watts
The induction of long-lived heterotypic T-cell protection against influenza virus remains elusive, despite the conservation of T-cell epitopes. T-cell protection against influenza is critically dependent on lung-resident memory T cells (Trm). Here we show that intranasal administration of 4-1BBL along with influenza nucleoprotein in a replication-defective adenovirus vector to influenza pre-immune mice induces a remarkably stable circulating effector memory CD8 T-cell population characterized by higher IL-7Rα expression than control-boosted T cells, as well as a substantial lung parenchymal CD69(+) CD8 Trm population, including both CD103(+) and CD103(-) cells...
January 4, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28039295/third-generation-cd28-4-1bb-chimeric-antigen-receptor-t-cells-for-chemotherapy-relapsed-or-refractory-acute-lymphoblastic-leukaemia-a-non-randomised-open-label-phase-i-trial-protocol
#9
Xiao-Yi Tang, Yao Sun, Ang Zhang, Guo-Liang Hu, Wei Cao, Dan-Hong Wang, Bin Zhang, Hu Chen
INTRODUCTION: There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain...
December 30, 2016: BMJ Open
https://www.readbyqxmd.com/read/28035433/development-of-t-cells-carrying-two-complementary-chimeric-antigen-receptors-against-glypican-3-and-asialoglycoprotein-receptor-1-for-the-treatment-of-hepatocellular-carcinoma
#10
Cheng Chen, Kesang Li, Hua Jiang, Fei Song, Huiping Gao, Xiaorong Pan, Bizhi Shi, Yanyu Bi, Huamao Wang, Hongyang Wang, Zonghai Li
Adoptive immunotherapy leveraging chimeric antigen receptor-modified T (CAR-T) cells holds great promise for the treatment of cancer. However, tumor-associated antigens often have low expression levels in normal tissues, which can cause on-target, off-tumor toxicity. Recently, we reported that GPC3-targeted CAR-T cells could eradicate hepatocellular carcinoma (HCC) xenografts in mice. However, it remains unknown whether on-target, off-tumor toxicity can occur. Therefore, we proposed that dual-targeted CAR-T cells co-expressing glypican-3 (GPC3) and asialoglycoprotein receptor 1 (ASGR1) (a liver tissue-specific protein)-targeted CARs featuring CD3ζ and 28BB (containing both CD28 and 4-1BB signaling domains), respectively, may have reduced on-target, off-tumor toxicity...
December 29, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28011265/involvement-of-ly6c-4-1bb-and-klrg1-in-the-activation-of-lamina-propria-lymphocytes-in-the-small-intestine-of-sanroque-mice
#11
Dina Montufar-Solis, Alexander Williams, Nadarajah Vigneswaran, John R Klein
Roquin is an E3 ligase that regulates mRNA stability. Mice with a mutation in the Rc3h1 gene and Roquin protein, referred to as Roquin(san/san) or sanroque mice, develop broad-spectrum chronic inflammatory conditions and autoimmune pathologies. Our laboratory recently reported that sanroque mice also develop extensive inflammation that is localized in the small intestine but is rare in the colon. Here, we demonstrate that small intestinal intraepithelial lymphocytes (IELs) are present in the epithelium of sanroque mice but that cell recoverability is low using standard extraction techniques even though lamina propria lymphocytes (LPLs) can be recovered in normal numbers...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28000531/cytokines-and-metabolic-factors-regulate-tumoricidal-t-cell-function-during-cancer-immunotherapy
#12
Adam J Adler, Payal Mittal, Joseph M Ryan, Beiyan Zhou, Jeffrey S Wasser, Anthony T Vella
Recent advances in cancer biology and genetics have fostered precision therapies targeting tumor-specific attributes. Immune-based therapies that elicit cytolytic T cells (CTL) specific for tumor antigens can provide therapeutic benefit to cancer patients, however, cure rates are typically low. This largely results from immunosuppressive mechanisms operating within the tumor microenvironment, many of which inflict metabolic stresses upon CTL. Conversely, immunotherapies can mitigate specific metabolic stressors...
January 2017: Immunotherapy
https://www.readbyqxmd.com/read/27777979/the-head-and-neck-cancer-immune-landscape-and-its-immunotherapeutic-implications
#13
Rajarsi Mandal, Yasin Şenbabaoğlu, Alexis Desrichard, Jonathan J Havel, Martin G Dalin, Nadeem Riaz, Ken-Wing Lee, Ian Ganly, A Ari Hakimi, Timothy A Chan, Luc G T Morris
Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation...
October 20, 2016: JCI Insight
https://www.readbyqxmd.com/read/27777771/expansion-of-tumor-infiltrating-lymphocytes-til-from-human-pancreatic-tumors
#14
MacLean Hall, Hao Liu, Mokenge Malafa, Barbara Centeno, Pamela J Hodul, José Pimiento, Shari Pilon-Thomas, Amod A Sarnaik
BACKGROUND: We evaluated whether tumor infiltrating lymphocytes (TIL) could be expanded from surgically resected tumors from pancreatic cancer patients. METHODS: Tumors were resected from pancreatic cancer patients. Tumors were minced into fragments and cultured in media containing high dose interleukin-2 (IL-2) for up to 6 weeks. T cell phenotype, activation markers, and reactivity were measured. RESULTS: TIL expansion was measured in 19 patient samples...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27760761/mva-vaccine-encoding-cmv-antigens-safely-induces-durable-expansion-of-cmv-specific-t-cells-in-healthy-adults
#15
Corinna La Rosa, Jeff Longmate, Joy Martinez, Qiao Zhou, Teodora I Kaltcheva, Weimin Tsai, Jennifer Drake, Mary Carroll, Felix Wussow, Flavia Chiuppesi, Nicola Hardwick, Sanjeet Dadwal, Ibrahim Aldoss, Ryotaro Nakamura, John A Zaia, Don J Diamond
Attenuated poxvirus modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding 3 immunodominant cytomegalovirus (CMV) antigens, which stimulates a host antiviral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination)...
January 5, 2017: Blood
https://www.readbyqxmd.com/read/27698940/blocking-the-4-1bb-pathway-ameliorates-crystalline-silica-induced-lung-inflammation-and-fibrosis-in-mice
#16
Chao Li, Sitong Du, Yiping Lu, Xiaowei Lu, Fangwei Liu, Ying Chen, Dong Weng, Jie Chen
Long term pulmonary exposure to crystalline silica leads to silicosis that manifests progressive interstitial fibrosis, eventually leading to respiratory failure and death. Despite efforts to eliminate silicosis, clinical cases continue to occur in both developing and developed countries. The exact mechanisms of crystalline silica-induced pulmonary fibrosis remain elusive. Herein, we find that 4-1BB is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis...
2016: Theranostics
https://www.readbyqxmd.com/read/27697858/il-2-variant-circumvents-icos-regulatory-t-cell-expansion-and-promotes-nk-cell-activation
#17
Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W Overwijk, Jason Roszik, Francesco M Marincola, Patrick Hwu, Elizabeth A Grimm, Laszlo G Radvanyi
Clinical responses to high-dose IL-2 therapy are limited due to selective expansion of CD4+CD25+oxp3+ T-regulatory cells (Tregs) especially ICOS+Tregs, rather than NK cells and effector T cells. These ICOS+Tregs are highly suppressive and constitutively express high levels of IL-2Ralpha (CD25) and CD39. Here, we characterized the effect of a mutant form of IL-2 (F42K), which preferentially binds to the lower affinity IL-2Rbetagamma with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets...
October 3, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27649551/ipilimumab-with-stereotactic-ablative-radiation-therapy-phase-i-results-and-immunologic-correlates-from-peripheral-t-cells
#18
Chad Tang, James W Welsh, Patricia de Groot, Erminia Massarelli, Joe Y Chang, Kenneth R Hess, Sreyashi Basu, Michael A Curran, Maria E Cabanillas, Vivek Subbiah, Siqing Fu, Apostolia M Tsimberidou, Daniel Karp, Daniel R Gomez, Adi Diab, Ritsuko Komaki, John V Heymach, Padmanee Sharma, Aung Naing, David S Hong
PURPOSE: Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab. EXPERIMENTAL DESIGN: SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27622011/combined-treatment-with-dabrafenib-and-trametinib-with-immune-stimulating-antibodies-for-braf-mutant-melanoma
#19
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27617959/forsythoside-a-inhibits-bvdv-replication-via-traf2-dependent-cd28-4-1bb-signaling-in-bovine-pbmcs
#20
Quan-Jiang Song, Xiao-Gang Weng, Dong-Jie Cai, Wang Zhang, Jiu-Feng Wang
Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea/mucosal disease (BVD/MD), is an important pathogen of cattle and other wild animals throughout the world. BVDV infection typically leads to an impaired immune response in cattle. In the present study, we investigated the effect of Forsythoside A (FTA) on BVDV infection of bovine peripheral blood mononuclear cells (PBMCs). We found that Forsythoside A could not only promote proliferation of PBMCs and T cells activation but also inhibit the replication of BVDV as well as apoptosis induced by BVDV...
2016: PloS One
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